Pharmaceutical Compositions

ABSTRACT

The present invention relates to pharmaceutical compositions comprising the antimuscarinic agent glycopyrrolate, for example the salt glycopyrronium bromide. In particular, the present invention relates to dry powder compositions which exhibit improved stability over time, and methods for producing the same.

The present invention relates to pharmaceutical compositions comprisingthe antimuscatinic agent glycopyrrolate, for example the saltglycopyrronium bromide. In particular, the present invention relates todry powder compositions which exhibit improved stability over time, andmethods for producing the same.

Glycopytrolate is an antimuscarinic agent which is useful in thetreatment of conditions such as chronic obstructive pulmonary disease(COPD), asthma, cystic fibrosis (CF) and related airway diseases. It isknown to provide glycopyrtolate formulations in the form of dry powderformulations, for administration using dry powder inhalers. Frequentlysalts of glycopyrrolate are used, such as glycopyrronium bromide.

The term “glycopyttolate” as used in connection with the presentinvention is intended to encompass salt forms or counterion formulationsof glycopyrrolate, such as glycopyrrolate bromide, as well as isolatedstereoisomers and mixtures of stereoisomers. Derivatives ofglycopyrrolate are also encompassed.

WO 01/76575 discloses the delivery of glycopyrrolate by dry powderinhaler. The formulation disclosed in this application may includemagnesium steatate to improve dispersion of the dry powder and to helpprolong the therapeutic effect by providing a controlled release of theglycopyrrolate. Studies show that this formulation may exert itstherapeutic effect for more than or less than 12 hours. WO 01/76575 alsodiscloses the use of magnesium stearate applied in a specific manner tothe surface of micronised glycopyrrolate particles, for subsequent usein an inhaled formulation with delayed release properties.

WO 00/28979 briefly discloses an example of a dry powder compositionincluding a combination of 0.2% w/w formoterol and 0.5% w/wglycopyrrolate and including 0.5% w/w magnesium stearate conventionallyblended in a tumble mixer with a lactose carrier (98.8% w/w). It isalleged that the magnesium stearate protects the formulation from thedeleterious effects of moisture ingress.

WO 96/23485, WO 01/78694, WO 01/78695, WO 02/43701 and WO 02/00197 alldisclose the use of magnesium stearate with any dry powder inhaledsystem for improving the dispersibility of the micronised drug particlesfrom the formulation, in comparison to a formulation in the absence ofsuch an additive. Additive materials which improve the dispersibility ofthe drug particles are often referred to as force control agents.

However, during development work with dry powder formulations for use indry powder inhalers for the treatment of COPD, asthma, CF and relatedairway diseases, it has been found that the above disclosures do notteach the satisfactory production of a robust and stable dry powderformulation of glycopyrrolate.

It has been found that glycopyrtolate which is generated as a micronisedpowder as taught in the prior art suffers from stability problems onstorage, even where the formulation includes an additive material forimproving dispersibility or for protecting against moisture, such asmagnesium stearate, as disclosed in WO 00/28979.

Indeed, glycopyrrolate has been found to have an acute problem withrespect to its stability, especially immediately following aconventional micronisation process. Micronisation of any drug, andspecifically here glycopyrrolate, may involve the injection of arelatively coarse source powder into a system which involves multiplehigh-speed collisions. Typically source powders of un-micronised drugwill exist in particle sizes substantially greater than 10 μm. Theobjective of the micronisation process is to reduce the primary particlesize to a size which is small enough to be delivered to the respiratoryairways. For example, it is known that a suitable size may be 10 to 0.1μm, and preferably 6 to 0.1 μm or 5 to 0.5 μm.

The multiple high-speed collisions are employed in micronisation toprovide the milling action required to break the particles down to therequired size. It is also well known that such milling action may alsoinduce the generation of non-crystalline material, especially on thesurface of the particles. Such non-crystalline material may be amorphousmaterial.

It has been found from studies of glycopyrronium bromide powder that thepresence of non-crystalline or amorphous glycopyrronium bromide materialcan lead to significant physical instability. This instability appearsdue to the aggressive uptake of water by the amorphous fraction, leadingto partial dissolution, and subsequent re-crystallization. Amorphousglycopyrrolate appears to aggressively take up water when stored atrelative humidities as low as 30%, indicating that the amorphousglycopyrrolate is inherently unstable even in conditions which arenormally considered to be “dry” conditions. Indeed, the uptake of only avery small amount of water (as little as approximately 4%) is believedto be sufficient to cause re-crystallisation. Thus, glycopyrrolate isextremely unstable compared to the majority of active agents, includingthose that are generally considered to be sensitive to moisture.

100% amorphous glycopyrrolate was obtained by lyophilisation. Thisamorphous glycopyrrolate was found to be very hygroscopic. Storing thisamorphous glycopyrrolate at ambient atmosphere (30-50% RH (relativehumidity)/21-25° C.) resulted in its transformation into a very stickymass within minutes. Confirmation of this hygroscopicity (at RH>0%) wasobtained by DVS (dynamic vapour sorption), which is a moisture sorptionanalysis, and after the experiment the amorphous was found to becrystalline and was a sintered solid.

The glass transition temperature by DSC (differential scanningcalorimetry) of a dry amorphous glycopyrrolate sample was at 65° C. Itis known from many substances that water acts as a plasticizer, i.e., itdepresses the glass transition temperature. It is anticipated that inthis case the glass transition may be depressed to below roomtemperature (at as little as 30-40% RH) and that crysytallizationoccurs. Prior to crystallization the sample becomes sticky.Consequently, it was concluded that re-crystallized parts which werepreviously amorphous will act as a form of glue between crystallineparts analogous to a sintering process.

Similarly, amorphous glycopyrrolate was formed by spray drying a 1%solution of the drug in water using a Büchi laboratory spray dryer.Immediately on collection of the powder within the collection cyclone,the powder formed a wet slurry and no dry powder could be recovered.

In a relatively short period of time, compared to that demanded forstorage of an inhaled product, moisture can be drawn in by thenon-crystalline material in a dry powder glycopyrrolate formulation,even in conditions which are generally considered to be relatively dry.The moisture absorption leads to the production of an intermediate wetform, followed by re-crystallization and possibly the release of anysurplus moisture not required by the newly formed crystalline structure.This process is likely to induce the formation of solid bridges atcontact points between the particles present. Where these bridges form,it has been found that they may be strong enough to result in asignificant reduction in the powder dispersibility.

It is therefore an aim of the present invention to provide a dry powdercomposition comprising glycopyrrolate which exhibits greater stabilitythan conventional dry powder glycopytrolate formulations. It is also anaim of the present invention to provide methods for consistently andreliably preparing stable dry powder compositions comprisingglycopyrrolate.

According to one aspect of the present invention, a dry powderformulation comprising glycopyrrolate is provided which is stable for aperiod of at least 1 year, more preferably a period of at least 2 yearsand most preferably a period of at least 3 years.

The glycopyrrolate may be a salt, isomer or derivative ofglycopyrrolate, or mixtures thereof. In one embodiment, theglycopyrrolate is not R,R-glycopyrrolate.

The stability of a composition should be indicated by consistentdispersability of the powder over these periods, which may, for example,be measured in terms of a consistently good fine particle fraction orfine particle dose over time. In one embodiment of the invention, thefine particle fraction (<5 μm) is consistently greater than about 30%over a period of at least 1 year, at least 2 years or at least 3 yearswhen stored at normal temperatures and humidities for pharmaceuticalproducts. In another embodiment of the invention, the fine particlefraction (<5 μm) is consistently greater than about 40% over a period ofat least 1 year, at least 2 years or at least 3 years. Preferably, thefine particle fraction (<5 μm) is consistently greater than 30% orgreater than 40% when the formulations are stored under standard testingconditions, such as 25° C./60% RH, 30° C./60% RH, 40° C./70% RH or 40°C./75% RH.

Preferably, the fine particle fraction of the dry powder formulations ofthe present invention is consistently at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70% or atleast about 80%.

Preferably, the fine particle dose of the dry powder formulations of thepresent invention is consistently at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70% or atleast about 80%.

In another embodiment of the invention, the dry powder formulations arepackaged for storage and/or delivery by a dry powder inhaler and thepackaged formulations are stable for at least 1, 2 or 3 years whenstored at normal temperatures and humidities, i.e. the packagedformulations or products comprising the formulations do not have to bestored in a controlled environment in order to exhibit the desiredstability.

As the instability of the conventional glycopyrrolate formulationsappears to be due to moisture absorption, there are a number of measureswhich are proposed to increase stability.

Firstly, the amorphous content of the glycopyrrolate is to be reduced byimproving the processing of the glycopyrrolate. Where the glycopyrrolateis micronised, the micronisation process may be improved, for example,by adjusting the conditions under which the milling takes place, toprevent the formation of amorphous material. Additionally oralternatively, the micronised product may be “conditioned” to remove theamorphous material.

Alternatively, the particles of glycopyrrolate may be engineered so thatthey include little or no amorphous material. Suitable methods for doingthis are known to those skilled in the art. For example, glycopyrrolatepowders with low non-crystalline content may be made using methods suchas supercritical fluid processing using carbon dioxide, or othercontrolled forms of crystallisation or precipitation, such as slowprecipitation, by emulsion methods, sono-crystallisation and the like.

Secondly, the exposure of the dry powder formulation to moisture whenthe powder is stored is preferably reduced. In this regard, it isparticularly desirable to reduce exposure of the formulation to moistureduring storage in capsules or blisters.

Finally, the inclusion of additive materials in the dry powderformulation can enhance the powder dispersability and protect theformulation from the ingress of moisture.

Batches of micronised glycopyrrolate were obtained and, following sealedstorage for several weeks, the physical changes of the material fromfine cohesive powders to solid agglomerates were observed.

The following section summarises the tests conducted on reported batchesof glycopyrrolate received following micronisation:

Batch A:

Micronised at 0.5 kg/hr

Injection pressure: 10 bar

Micronisation pressure: 7 bar

Sympatec sizing: d10 0.7 μm, d50 1.8 μm, d90 3.6 μm

Loss on drying: 0.7%

DVS indicated crystalline material. On storage, soft lumps of materialwere found in bulk powder, and repeated particle sizing gave d50 valuesranging between 2.6 and 3.5 cm.

Batch B:

Micronised at 0.5 kg/hr

Injection pressure: 10 bar

Micronisation pressure: 7 bar

Sympatec sizing: d10 1.0 μm, d50 2.4 μm, d90 4.8 μm

Loss on drying: 0.6%

Water activity: 54% RH

DVS indicated amorphous material was present. On storage, large hardlumps of material were found, and repeated particle sizing gave d50values ranging between 36 and 160 μm.

Batch C:

Micronised at 0.4 kg/hr

Injection pressure: 10 bar

Micronisation pressure: 9.8 bar

Sympatec sizing: d10 0.8 μm, d50 2.3 μm, d90 4.8 μm

Loss on drying: 0.4%

DVS indicated amorphous material was present. On storage, large hardlumps of material were found in bulk powder, and repeated particlesizing gave d50 value of 51 μm.

Remicronised Batch C:

Micronised at 0.5 kg/hr

Injection pressure: 10 bar

Mictonisation pressure: 9 bar

Sympatec sizing: d10 1.0 μm, d50 2.4 μm, d90 4.5 μm

Loss on drying: 0.5%

On storage, only soft lumps of material were found in bulk powder.

This summary shows that selected batches of micronised glycopyrrolatehad formed hard agglomerates, and this appears to be associated with thepresence of amorphous material, as the first batch, which contained nodetectable amorphous material, exhibited good powder propertiesfollowing storage. Consequently, it is believed that the formation ofhard agglomerates occurs within a micronised powder that containssurface non-crystalline material, whether formulated with excipient, anymoisture protection agent, a force control agent, or on its own.

The amorphous material will be located on the surface to have thegreatest effect of this kind. The quantity of amorphous materialrelative to the bulk mass may be very small, as long as it is sufficientto produce this effect. The non-crystalline material will draw moisturefrom its surroundings. Sources of moisture may include the surroundingair or gas, the surrounding excipients or additives (such as lactose orforce control agents), the packaging or device, such as a gelatin orother capsule material, or a plastic.

Tests have shown that all micronised glycopyrronium bromide prototypeformulations made using conventional methods, including those thatcomprise additives (including magnesium stearate), disclosed in theprior art as noted above, have been found to degrade or deteriorate inaerosolisation performance over a period of 6 months. This deteriorationhas even been found to occur when stored under dry conditions.Deterioration in performance has been seen to be approximately 30 to 50%of original performance or more. Such deterioration would make theseformulations unattractive for commercial use.

It has been suggested that conducting micronisation under the use ofhumidified air or other gas may help to reduce the generation ofamorphous materials. Both WO 99/54048 and WO 00/32165 disclose thatmilling under increased humidity can reduce the generation of amorphousmaterial. WO 00/32313 discloses the milling of material at reducedtemperature using helium or a mixture of helium and another gas in orderto reduce the formation of amorphous material. It should be noted thatnone of these prior art documents disclose that the milling ofglycopyrrolate under these special conditions is beneficial.

However, the milling conditions disclosed in the prior art are notstandard in micronisation practice and it may well prove to be difficultto control these processes. It may also prove difficult to use suchprocesses on a commercial scale. Finally, the extent to which suchprocesses may help to control the generation of amorphous material forthe specific problem of glycopyrrolate is also not known. As mentionedabove, glycopyrrolate presents particular problems because of itsinherent instability.

In accordance with one embodiment of the present invention, the drypowder formulation comprising glycopyrrolate is prepared using aprocess, preferably a micronisation process, which is carried out underconditions which reduce the formation of amorphous material. Examples ofsuitable micronisation conditions include increased relative humidity(for example 30-70%) or micronisation using helium at reducedtemperatures.

In another embodiment, the dry powder formulation comprisingglycopyrrolate is micronised and then undergoes a “conditioning” step toremove or reduce the amorphous material content. Such conditioning stepsinclude exposure to moisture to encourage re-crystallisation of theamorphous material without the formation of hard agglomerates. Examplesof such conditioning are discussed in more detail below.

It is known for gelatin capsules to contain in the order of 10 to 15%water, and for this to provide a sufficient source of water to create amoisture instability problem. The moisture content of the gelatincapsules has been shown to drop as the water is extracted by the capsulecontents. The water content in the gelatin capsules acts as aplasticizer so that when the water is extracted and the water contentdrops, the capsules become more brittle, which will affect piercing andthe like.

A recent article on improvements in hypromellose capsules (B. E. Jones,Drug Delivery Technology, Vol 3 No. 6, page 2, 2003), describes theproblems associated with gelatin capsules for use in dry powderinhalers. These problems include changes in brittleness and hencepiercing consistency, and related dispersion performance as a functionof the changes in gelatin moisture content. The potential of the gelatinto act as a moisture source, which can be released to the powderedcontents of the capsule, is also discussed, as are the variations inelectrostatic charge properties.

Capsules can be made with hypromellose (HPMC) or other celluloses orcellulose derivatives which do not rely on moisture as a plasticizer.The moisture content of such capsules can be less than 10%, or evenbelow 5% or 3%, and this makes such capsules more suitable for use withglycopyrrolate.

Capsules can also be made from gelatin containing one or moreplasticizers other than water, such as PEG, glycerol, sorbitol,propyleneglycol or other similar polymers and co-polymers, henceallowing the moisture content to be reduced to below 10%, or even below5% or 3%.

Alternatively, capsules can be made from synthetic plastics orthermoplastics (polyethylene or polycarbonate or related plastics)containing reduced moisture content below 10%, or even below 5% or 3%.Further alternative capsules with reduced moisture content are made fromstarch or starch derivatives or chitosan.

In the foregoing capsules, the problem of brittleness is reduced.Furthermore, capsules such as those made from celluloses have been foundto pierce more consistently and reliably, and the pierce hole madeappears to be more cleanly formed and spherical, with less shedding ofparticles. The aerosolisation of the powder contents has also been foundto be improved, as well as being more consistent.

In an further approach to solving the problem of moisture absorption bydry powder glycopyrrolate formulations, an inhaler device is used whichincludes a means for protecting the formulation from moisture, forexample within a sealed blister, such as a foil blister, with suitablesealing to prevent the ingress of moisture. Such devices are known, forexample the GyroHaler (Vectura) or Diskus (GSK) devices. It is believedto be particularly advantageous if the blister is pierced using a simplemechanism, such as with the GyroHaler. This device has been developed byVectura and it is an inhalation device for oral or nasal delivery of amedicament in powdered form. The powdered medicament is stored in astrip of blisters and each blister has a puncturable lid. When theinhaler is to be used, the lid of the aligned blister is punctured,thereby allowing an airflow through the blister to be generated toentrain the dose contained therein and to carry the dose out of theblister and into the user's airway via the inhaler mouthpiece. Thisarrangement with blisters having puncturable lids allows the blisters tohave the best possible seal. In contrast, in blister systems such as theDiskus where the lids of the blisters are peeled open, it is moredifficult to maintain an optimum seal due to the restrictions on thenature of the bond required to allow peeling to occur.

Thus, in a further embodiment of the present invention, the dry powderformulation comprising glycopyrrolate is stored in packaging made from amaterial which itself has a moisture content of less than 10%,preferably less than 5% and more preferably less than 3%.

The packaging should also preferably prevent the ingress of moisture, sothat the powder is protected from external sources of moisture. Foilsealed blisters are en example of a packaging which prevents ingress ofmoisture.

In this latter regard, the prevention of the ingress of moisture fromexternal sources may be assisted by further packaging. For example, HPMCcapsules may be stored in a sealed environment, such as an additionallayer of foil packaging.

In an alternative embodiment, the dry powder formulation is dispensedfrom a multidose dry powder inhaler device wherein the powder is storedin a reservoir as opposed to individually packaged doses. In such anembodiment, the device should offer superior moisture protectioncompared to conventional reservoir devices. For example, the deviceshould include one or more of the following features: a sealed reservoirchamber (for example including a sealing gasket to seal the reservoirchamber), plastics materials exhibiting very low moisture permeability(for forming the walls of the reservoir chamber), and a desiccant.

In a yet further embodiment of the present invention, the dry powderformulation comprising glycopyrrolate further comprises an additivematerial, such as a so-called force control agent. A force control agentis an agent which reduces the cohesion between the fine particles withinthe powder formulation, thereby promoting deagglomeration upondispensing of the powder from the dry powder inhaler. Suitable forcecontrol agents are disclosed in WO 96/23485 and they preferably consistof physiologically acceptable material, despite the fact that thematerial may not always reach the lung.

The force control agent may comprise or consist of one or more compoundsselected from amino acids and derivatives thereof, and peptides andderivatives thereof, the peptides preferably having a molecular weightfrom 0.25 to 1000 Kda. Amino acids, peptides and derivatives of peptidesare physiologically acceptable and give acceptable release ordeagglomeration of the particles of active material on inhalation. Wherethe force control agent comprises an amino acid, it may be one or moreof any of the following amino acids: leucine, isoleucine, lysine,valine, methionine, and phenylalanine. The force control agent may be asalt or a derivative of an amino acid, for example aspartame oracesulfame K. The D- and DL-forms of amino acids may also be used.

The force control agents may include one or more water solublesubstances. This helps absorption of the force control agent by the bodyif it teaches the lower lung. The force control agent may includedipolar ions, which may be zwitterions. It is also advantageous toinclude a spreading agent as a force control agent, to assist with thedispersal of the composition in the lungs. Suitable spreading agentsinclude surfactants such as known lung surfactants (e.g. ALEC,Registered Trade Mark) which comprise phospholipids, for example,mixtures of DPPC (dipalmitoyl phosphatidylcholine) and PG(phosphatidylglycerol). Other suitable surfactants include, for example,dipalmitoyl phosphatidylethanolamine (DPPE), dipalmitoylphosphatidylinositol (DPPI).

The force control agent may comprise a metal stearate, or a derivativethereof, for example, sodium stearyl fumarate or sodium stearyllactylate. Advantageously, it comprises a metal steatate. For example,zinc stearate, magnesium stearate, calcium stearate, sodium stearate orlithium stearate. Preferably, the additive material comprises orconsists of magnesium stearate.

The force control agent may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble or water dispersible, forexample lecithin, in particular soya lecithin, or substantially waterinsoluble, for example solid state fatty acids such as oleic acid,lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, orderivatives (such as esters and salts) thereof such as glycerylbehenate. Specific examples of such materials are phosphatidylcholines,phosphatidylethanolamines, phosphatidylglycerols and other examples ofnatural and synthetic lung surfactants; lauric acid and its salts, forexample, sodium lauryl sulphate, magnesium lauryl sulphate;triglycerides such as Dynsan 118 and Cutina HR; and sugar esters ingeneral. Alternatively, the force control agent may be cholesterol.

Other possible force control agents include sodium benzoate,hydrogenated oils which are solid at room temperature, talc, titaniumdioxide, aluminium dioxide, silicon dioxide and starch. Also useful asforce control agents are film-forming agents, fatty acids and theirderivatives, as well as lipids and lipid-like materials.

Force control agents which are particularly suitable for use in thepresent invention include magnesium stearate, amino acids includingleucine, lysine, arginine, histidine, cysteine and their derivatives,lecithin and phospholipids. The inclusion of these force control agentsis expected to improve the efficacy of the glycopyrrolate for treatingrespiratory disorders such as COPD, asthma or CF.

Further, it is believed to be important for any force control agent tobe predominantly present on the surface of the glycopyrrolate particles,as well as or rather than being on the surface of the carrier particles.It has been found that a high shear blending method is advantageous toachieve this.

In addition to reducing the cohesion between the fine particles of theglycopyrrolate formulation, additive materials, including the forcecontrol agents mentioned above, may have further benefits when used inthe present invention. It has been suggested that some force controlagents, such as magnesium stearate, are able to themselves reduce theingress of moisture into the dry powder formulation. Furthermore, manyforce control agents act as surfactants. When these agents areadministered to the lung, they tend to rapidly spread over the surfaceof the lung. It is postulated that this rapid dispersion of thesurfactants may well assist in the dispersion of the glycopyrrolate inthe formulation, thereby assisting and enhancing its therapeutic effect.

From the foregoing it can be seen that the desired improvements in thefine particle fraction of dry powder formulations containingglycopyrrolate for a period suitable for an inhalation product (e.g. 1,2, 3 years) can be achieved by suitable conditioning, and/or byprotection of the formulation from moisture, and/or by the suitableincorporation of an additive, such as a force control agent. Indeed, asthe examples discussed below indicate, a combination of two or more ofthese measures leads to the best results. The protection of the drypowder formulation from moisture may be particularly important.

A very important advantage of the present invention is that it allowsthe administration of smaller doses than previously used. The reductionof the dose is made possible by the more consistent and predictableadministration of the glycopyrrolate, for example, through aconsistently improved fine particle fraction and fine particle dosecompared to that observed in connection with the conventionalformulations. Consequently, while the dose dispensed is smaller, theamount of active agent being administered is the same, with the sametherapeutic effect being achieved.

The formulations of the present invention may include glycopyrrolate asthe only pharmaceutically active agent. Alternatively, the formulationsmay include one or more further active agents, in addition to theglycopyrrolate. The additional active agents may include, for example:

1) steroid drugs such as, for example, alcometasone, beclomethasone,beclomethasone dipropionate, betamethasone, budesonide, clobetasol,deflazacort, diflucortolone, desoxymethasone, dexamethasone,fludrocortisone, flunisolide, fluocinolone, fluometholone, fluticasone,fluticasone propionate, hydrocortisone, triamcinolone, nandrolonedecanoate, neomycin sulphate, rimexolone, methylprednisolone andprednisolone;

2) antibiotic and antibacterial agents such as, for example,metronidazole, sulphadiazine, triclosan, neomycin, amoxicillin,amphotericin, clindamycin, aclarubicin, dactinomycin, nystatin,mupirocin and chlorhexidine;

3) systemically active drugs such as, for example, isosorbide dinitrate,isosorbide mononitrate, apomorphine and nicotine;

4) antihistamines such as, for example, azelastine, chlorpheniramine,astemizole, cetitizine, cinnatizine, desloratadine, loratadine,hydroxyzine, diphenhydramine, fexofenadine, ketotifen, promethazine,trinmeprazine and terfenadine;

5) anti-inflammatory agents such as, for example, piroxicam, nedocromil,benzydamine, diclofenac sodium, ketoprofen, ibuprofen, heparinoid,nedocromil, cromoglycate, fasafungine and iodoxamide;

6) anticholinergic agents such as, for example, atropine, benzatropine,bipetiden, cyclopentolate, oxybutinin, orphenadine hydrochloride,procyclidine, propantheline, propiverine, tiotropium, tropicamide,trospium, ipratropium bromide and oxitroprium bromide;

7) anti-emetics such as, for example, bestahistine, dolasetron,nabilone, prochlorperazine, ondansetron, trifluoperazine, tropisetron,domperidone, hyoscine, cinnarizine, metoclopramide, cyclizine,dimenhydrinate and promethazine;

8) hormonal drugs such as, for example, protirelin, thyroxine,salcotonin, somatropin, tetracosactide, vasopressin or desmopressin;

9) bronchodilators, such as salbutamol, fenoterol, formoterol andsalmeterol;

10) sympathomimetic drugs, such as adrenaline, noradrenaline,dexamfetamine, dipirefin, dobutamine, dopexamine, phenylephrine,isoprenaline, dopamine, pseudoephedrine, tramazoline and xylometazoline;

11) anti-fungal drugs such as, for example, amphotericin, caspofungin,clotrimazole, econazole nitrate, fluconazole, ketoconazole, nystatin,itraconazole, terbinafine, voriconazole and miconazole;

12) local anaesthetics such as, for example, amethocame, bupivacaine,hydrocortisone, methylprednisolone, prilocalne, proxymetacaine,ropivacaine, tyrothricin, benzocaine and lignocaine;

13) opiates, preferably for pain management, such as, for example,buprenorphine, dextromoramide, diamotphine, codeine phosphate,dextropropoxyphene, dihydrocodeine, papavereturn, pholcodeine,loperamide, fentanyl, methadone, morphine, oxycodone, phenazocine,pethidine and combinations thereof with an anti-emetic;

14) analgesics and drugs for treating migraine such as clonidine,codine, coproxamol, dextropropoxypene, etgotamine, sumatriptan, tramadoland non-steroidal anti-inflammatory drugs;

15) narcotic agonists and opiate antidotes such as naloxone, andpentazocine;

16) phosphodiestetase type 5 inhibitors, such as sildenafil; and

17) pharmaceutically acceptable salts of any of the foregoing.

Preferably, the additional active agents are pharmaceutically activeagents which are known to be useful in the treatment of respiratorydisorders, such as β₂-agonists, steroids, anticholinergics,phosphodiesterase 4 inhibitors, and the like. In one embodiment, theformulation of the present invention does not include formoterol. Thefollowing examples serve to support the invention discussed above.

EXAMPLE 1 Formulation A

The blend comprised mictonised glycopyrronium bromide, with Pharmatose150M (DMV), blend to give a 60 μg dose.

Formulation B

The blend comprised micronised glycopyrronium bromide, with Pharmatose150M (DMV), blend to give a 120 μg dose.

Formulation C

The blend comprised micronised glycopyrronium bromide, with Pharmatose150M (DMV), blend to give a 60 μg dose.

Formulation D

The blend comprised micronised glycopyrronium bromide, with Pharmatose150M (DMV), blend to give a 120 μg dose.

Formulation E

The blend comprised micronised glycopyrronium bromide, with Pharmatose150M (DMV), blend to give a 60 μg dose.

Formulation F

The blend comprised micronised glycopyrronium bromide, with Pharmatose150M (DMV), blend to give a 120 μg dose.

These powders were then loaded as the appropriate doses of 60 μg and 120μg into gelatin capsules. These were then packaged and stored underselected conditions of 40° C./70% RH, 30° C./60% RH and 25° C./60% RH.

The fine particle fraction was assessed by firing the capsules from aMiat MonoHaler device into a multi stage liquid impinger, using themethod defined in the European Pharmacopoeia 4^(th) Edition 2002.Delivered dose (DD), fine particle dose (FPD) and fine particle fraction(FPF) were measured. The fine particle fraction was defined here as themass fraction smaller than 5 μm relative to the delivered dose in eachcase. Delivered dose (DD) was also assessed by collection into a DUSAtube using the method defined in the European Pharmacopoeia 2002. Testswere conducted at selected time-points of up to 9 months and the resultsare summarised in the following Tables: Stability of Formulation A (60μg), stored at 25° C./60% RH Time DUSA MSLI (months) DD (μg) DD (μg) FPD(μg) FPF (%) 0 52 53 24 45 1 51 50 19 39 2 55 51 20 39 3 53 53 21 40 646 50 20 40

Stability of Formulation A (60 μg), stored at 40° C./70% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 52 53 24 45 1 47 49 1735 2 46 46 14 31 3 45 44 13 30

Stability of Formulation B (120 μg), stored at 25° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 107 107 48 45 1 102 10445 43 2 104 105 44 42 3 110 111 44 40 6 102 108 45 42

Stability of Formulation B (120 μg), stored at 40° C./70% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 107 107 48 45 1 105 10437 36 2 101 101 36 36 3 97 97 27 28

Stability of Formulation C (60 μg), stored at 25° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 50 49 17 34 4 — 49 1632 9 44 43 13 29

Stability of Formulation C (60 μg), stored at 30° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 50 49 17 34 9 43 45 1227

Stability of Formulation D (120 μg), stored at 25° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 97 105 32 31 4 — 99 2829 9 99 97 23 24

Stability of Formulation D (120 μg), stored at 30° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) 0 97 105 32 31 9 99 98 2425

Stability of Formulation E (60 μg), stored at 25° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) Release 45 51 16 31 Setdown* 48 52 14 26 Set down + 4 45 47 10 20*Set down was 3 months after release date

Stability of Formulation E (60 μg), stored at 30° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) Release 45 51 16 31 Setdown* 48 52 14 26 Set down + 4 48 48 10 21*Set down was 3 months after release date

Stability of Formulation F (120 μg), stored at 25° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) Release 97 107 33 31 Setdown* 102 108 31 29 Set down + 99 105 24 23 4*Set down was 3 months after release date

Stability of Formulation F (120 μg), stored at 30° C./60% RH Time DUSAMSLI (months) DD (μg) DD (μg) FPD (μg) FPF (%) Release 97 107 33 31 Setdown* 102 108 31 29 Set down + 103 106 23 22 4*Set down was 3 months after release date

It can be seen from this stability study, that all of the formulationsdropped in FPF performance during the stability period when stored at30° C./60% RH or 40° C./75% RH. However, at 25° C./60% RH, FormulationsA and B had a relatively small drop in FPF compared to the otherformulations, which dropped more sharply.

Formulations A and B also had a substantially greater FPF at the releasecompared to the other formulations, indicating large variation betweenthese otherwise similar blends.

EXAMPLE 2 Formulations Targeted at 480 μg with Magnesium Stearate

Formulation 1

This blend comprised 90% of Capsulac large carrier lactose, 7.8%Sorbolac 400, 0.25% magnesium stearate and 1.92% micronisedglycopyrronium bromide. The Sorbolac 400 lactose was mixed with themagnesium stearate and the micronised glycopyrronium bromide in aKenwood Mini Chopper high shear blender for 5 minutes. At 1 minuteintervals the walls of the blender were swept down to optimise mixing.

This pre-blend was then sandwiched between 2 layers of the Capsulaclarge carrier lactose in a capsule shaped vessel, and then Turbulablended for 1 hour at 42 rpm, followed by 10 minutes at 62 rpm toimprove content uniformity.

Formulation 2

This blend comprised 90% of Pharmatose 325 large carrier lactose, 7.8%Sorbolac 400, 0.25% magnesium stearate and 1.92% micronisedglycopyrronium bromide. The Sorbolac 400 lactose was mixed with themagnesium stearate and the micronised glycopyrronium bromide in aKenwood Mini Chopper high shear blender for 5 minutes. At 1 minuteintervals the walls of the blender were swept down to optimise mining.

This pre-blend was then sandwiched between 2 layers of the Pharmatose325 large carrier lactose in a capsule shaped vessel, and then Turbulablended for 1 hour at 42 rpm.

Formulations 3 and 4 (Repeated)

These repeated blends comprised 90% of Pharmatose 325 large carrierlactose, 7.8% Sorbolac 400, 0.25% magnesium stearate and 1.92%micronised glycopyrronium bromide. The Sorbolac 400 lactose was mixedwith the magnesium stearate and the Pharmatose 325 large carrier lactosein a GrindoMix high shear blender for 1 minute at 2000 rpm. This wasleft for 1 hour to reduce electrostatic charge within the powder mass.

Micronised glycopyrronium bromide was then sandwiched between 2 layersof this pre-blend in the GrindoMix, and blended for 5 minutes at 2000rpm.

Formulations 5 and 6 (Repeated)

These repeated blends comprised 90% of Pharmatose 150 large carrierlactose, 7.8% Sorbolac 400, 0.25% magnesium stearate and 1.92%micronised glycopyrronium bromide. The Sorbolac 400 lactose was mixedwith the magnesium stearate and the Pharmatose 150 large carrier lactosein a GrindoMix high shear blender for 1 minute at 2000 rpm. This wasleft for 1 hour to reduce electrostatic charge within the powder mass.

Micronised glycopyrronium bromide was then sandwiched between 2 layersof this pre-blend in the GrindoMix, and blended for 5 minutes at 2000rpm, followed by a further 4 minutes to improve blend contentuniformity.

Formulation 7

This blend comprised approximately 90% of Pharmatose 150 large carrierlactose, 7.9% Sorbolac 400, 0.15% magnesium stearate and 1.9% micronisedglycopyrronium bromide. The Sorbolac 400 lactose was mixed with themagnesium stearate and the Pharmatose 150 large carrier lactose in aGrindoMix high shear blender for 1 minute at 2000 rpm. This was left for1 hour to reduce electrostatic charge within the powder mass.

Micronised glycopyrronium bromide was then sandwiched between 2 layersof this pre-blend in the GrindoMix, and blended for 9 minutes at 2000rpm.

Formulations Targeted at 480 μg without Magnesium Stearate

Formulation 8

This blend comprised 90.25% of Pharmatose 325 large carrier lactose,7.8% Sorbolac 400, and 1.92% micronised glycopyrronium bromide. TheSorbolac 400 lactose was mixed with the Phatmatose 325 large carrierlactose in a GrindoMix high shear blender for 1 minute at 2000 rpm. Thiswas left for 1 hour to reduce electrostatic charge within the powdermass.

Micronised glycopyrronium bromide was then sandwiched between 2 layersof this pre-blend in the GrindoMix, and blended for 7 minutes at 2000rpm.

Formulation 9

This blend comprised 90.25% of Pharmatose 150 large carrier lactose,7.8% Sorbolac 400, and 1.92% micronised glycopyrronium bromide. TheSorbolac 400 lactose was mixed with the Pharmatose 325 large carrierlactose in a GrindoMix high shear blender for 1 minute at 2000 rpm. Thiswas left for 1 hour to reduce electrostatic charge within the powdermass.

Micronised glycopyrronium bromide was then sandwiched between 2 layersof this pre-blend in the GrindoMix, and blended for 7 minutes at 2000rpm.

Powder Testing

All formulations manufactured were assessed for satisfactory bulk powdercontent uniformity.

The fine particle fraction was assessed by firing the capsules from aMiat MonoHaler device into a multi stage liquid impinger (MSLI), usingthe method defined in the European Pharmacopoeia 4^(th) Edition 2002.Five consecutive doses were collected under an operating air flow of 100l/min. CITDAS software was used to process the stage deposition data,and to generate delivered dose (DD), fine particle dose <5 μm (FPD) andfine particle fraction <5 μm (FPF).

The results are summarised in the following table. MSLI PerformanceFormulation DD (μg) FPD (μg) FPF (%) 1 367 114 31 2 385 86 22 3 350 15945 4 384 179 46 5 406 233 57 6 420 229 54 7 404 216 53 8 390 148 38 9398 177 44

The data show that formulations manufactured without magnesium stearateas a force control agent exhibited approximately 20% reduction in fineparticle fraction and dose than the respective formulations with a forcecontrol agent. For example, Formulation 8 without a force control agentexhibited a FPF of 38%, Formulation 4 with a force control agent a FPFof 46%, Formulation 9 without a force control agent a FPF of 44% andFormulation 5 with a force control agent exhibited a FPF of 57%.

The formulations manufactured with 0.15% force control agent had aslightly lower performance than those with 0.25% force control agent(FPF of 53% compared to FPFs of 57% and 54%).

In general, the formulations in Example 2 with magnesium stearate showbetter FPF values than those in Example 1 without magnesium stearate.

The repeated formulations in Example 1 without magnesium stearate showgreater variation in FPF than the repeated formulations in Example 2

Blend content uniformity did not seem to be affected by addition of aforce control agent, but was affected by insufficient mixing, related tothe lower energy blending methods or insufficient blending time.Similarly, aerosol dispersion characteristics were substantially worsefor blends made with the lower energy blending process, that is, Turbulablends exhibited FPFs of 22-31% whilst high shear blends exhibited FPFsof 45-57%.

Dispersion performance for blends using Pharmatose 150M were improvedover those using Pharmatose 325. This may be attributed to the increasedfine lactose (i.e., %<40 μm) content for the Pharmatose 150M material.Performance was consistent at 25 mg and 12.5 mg capsule loadings.

Consequently, it can be concluded that the optimum performance required:

High Shear Blending;

Magnesium stearate content >0.05%, more preferably >0.1% but preferablynot enough to create CU or toxicity problems (e.g. preferably <5%, morepreferably <2%, more preferably <1%, and more preferably <0.5%); andFine lactose content preferably >3%, more preferably >5% more preferably>8%.

EXAMPLE 3

Subsequent to this work, blends containing 400 μg, 250 μg and 20 μgglycopyrrolate were made using the following method.

This blend comprised approximately 90% of Pharmatose 150 large carrierlactose, approximately 9% Sorbolac 400, 0.15% magnesium stearate and themicronised glycopyrronium bromide. The Sorbolac 400 lactose was mixedwith the magnesium stearate and the Pharmatose 150 large carrier lactosein a GrindoMix high shear blender for 1 minute at 2000 rpm. This wasleft for 1 hour to reduce electrostatic charge within the powder mass.

Micronised glycopyrronium bromide was then sandwiched between 2 layersof this pre-blend in the GrindoMix, and blended for 9 minutes at 2000rpm.

These powders were then loaded as the appropriate doses of 400 μg, 250μg and 20 μg into gelatin capsules, and packaged in foil pouches. Thesewere then stored under conditions of 40° C./75% RH, 30° C./60% RH and25° C./60% RH. The fine particle fraction was assessed by firing thecapsules from a Miat MonoHaler device into a multi stage liquidimpinger, using the method defined in the European Pharmacopoeia 4^(th)Edition 2002. The fine particle fraction was defined here as the massfraction smaller than 5 μm relative to the nominal dose in each case.Selected tests were conducted at time-points of up to 52 weeks.

The data are summarised in the following tables. AerodynamicAssessment - FPF (ND) % Time (weeks) 400 μg 40° C./75% RH Packaged inFoil Pouch 0 42.6 ± 1.3 4 30.1 ± 1.9 12 26.5 ± 1.4 31 23.9 ± 2.6 400 μg30° C./60% RH Packaged in Foil Pouch 0 42.6 ± 1.3 4 41.4 ± 0.9 12 40.7 ±1.3 31 36.7 ± 1.1 42 38.4 ± 0.9 52 38.4 ± 0.8 400 μg 25° C./60% RHPackaged in Foil Pouch 0 42.6 ± 1.3 12 42.0 ± 2.4 31 39.0 ± 2.5 42 44.9± 0.3 52 40.3 ± 1.2

Aerodynamic Assessment - FPF (ND) % Time (weeks) 250 μg 40° C./75% RHPackaged in Foil Pouch 0 39.5 ± 2.0 4 27.6 ± 0.7 12 21.3 ± 1.1 31 19.9 ±0.6 250 μg 30° C./60% RH Packaged in Foil Pouch 0 39.5 ± 2.0 4 40.2 ±1.5 12 35.6 ± 2.1 31 31.1 ± 2.5 42 36.9 ± 0.5 52 32.2 ± 4.4 250 μg 25°C./60% RH Packaged in Foil Pouch 0 39.5 ± 2.0 12 39.2 ± 2.9 31 39.0 ±1.5 42 39.1 ± 0.6 52 34.5 ± 1.1

Aerodynamic Assessment - FPF (ND) % Time (weeks) 20 μg 40° C./75% RHPackaged in Foil Pouch 0 42.3 ± 1.9 4 20.8 ± 1.1 8 18.4 ± 0.9 12 — 20 μg30° C./60% RH Packaged in Foil Pouch 0 42.3 ± 1.9 4 35.5 ± 1.4 8 29.0 ±0.3 12 28.8 ± 0.5 20 μg 25° C./60% RH Packaged in Foil Pouch 0 42.3 ±1.9 4 39.1 ± 0.4 8 41.2 ± 0.4 12 37.3 ± 0.2 23 36.2 ± 1.7 26 31.0 ± 0.540 31.8 ± 1.0 52 32.8 ± 1.3

In each case, the FPF value at the initial time-point was approximately40%. However, in each case, the material stored at 40° C./75% RH, theFPF had dropped to below 30% after 4 weeks, and in most cases toapproximately 20% after 12 weeks. The 250 μg the material stored at 30°C./60% RH, the FPF had dropped to nearly 30% after 31 weeks, and the 20μg the material stored at 30° C./60% RH, the FPF had dropped to below30% after 8 weeks.

The 250 μg the material stored at 25° C./60% RH, the FPF had dropped tonearly 35% after 52 weeks, and the 200 μg the material stored at 25°C./60% RH, the FPF had dropped to about 30% after 26 weeks.

Consequently, it was concluded that magnesium stearate was not providingprotection from instability in these prototype formulations. A number ofmeasures were proposed:

-   -   To increase the magnesium stearate level    -   To condition the drug by a pre-exposure to moisture    -   To condition the excipients and additives by a pre-exposure to a        low moisture environment    -   To condition the capsules by a pre-exposure to a low moisture        environment    -   To employ low moisture content (e.g. HPMC) capsules    -   To investigate foil aluminium overwrap.

EXAMPLE 4

In this new study, blends containing 160 μg, 80 μg, 40 μg and 20 μgglycopyrrolate are to be made using the following method. The blendscomprise approximately 90% of Pharmatose 150 large carrier lactose,between approximately 9 and 9.8% Sorbolac 400, 0.15% magnesium stearateand the micronised glycopyrronium bromide. The powders are blended in ahigh shear mixer, in one step. These powders are preconditioned at 40%RH.

EXAMPLE 5

Blends containing 250 μg and 20 μg glycopyrrolate in 25 mg were madeusing the method described in Example 3. Powders were made with 0.15%magnesium stearate. 25 mg of the powders were then loaded into HPMCcapsules and into gelatin capsules, and packaged in cold form aluminiumfoil pouches. The gelatin capsules had been pre-conditioned at 40% RH.

These were then stored under conditions of 30° C./65% RH. The fineparticle fraction was assessed by firing the capsules from a MiatMonoHaler device into a multi stage liquid impinger, using the methoddefined in the European Pharmacopoeia 2002. Delivered dose (DD), fineparticle dose (FPD) and fine particle fraction (FPF) were measured. TheFPF was defined here as the mass fraction smaller than 5 μm relative tothe nominal dose in each case. Delivered dose (DD) was also assessed bycollection into a DUSA tube using the method defined in the EuropeanPharmacopoeia 2002.

Powders were tested at the start point and at selected timepoints of oneand three months. The results of the tests are summarised below: With0.15% Magnesium Stearate and 250 μg Glycopyrrolate re- CT re-micronisedmicronised Pre-cinical Gelatin HPMC Gelatin Gelatin t = 0 0.15% 0.15%0.15% 0.15% DD 215.9 ± 3.7 214.9 ± 7.7 203.5 ± 2.8 192.7 ± 6.6 FPD 106.1± 2.6 116.8 ± 6.3 100.5 ± 2.3  98.8 ± 4.9 (μg) FPF  42.4 ± 1.0  46.7 ±2.5  40.2 ± 0.9  39.5 ± 2.0 (%) DUSA  204.7 ± 12.4 N/A N/A  188.4 ± 16.7Gelatin t = 1 Gelatin HPMC Gelatin 0.15% 30/65 0.15% 0.15% 0.15% 30/60DD 196.2 ± 6.8 209.3 ± 2.3 176.1 ± 5.7 202.7 ± 8.4 FPD  75.2 ± 7.2111.05 ± 1.6   66.0 ± 2.6 100.4 ± 3.7 (μg) FPF  30.1 ± 2.9  44.4 ± 0.6 26.4 ± 1.1  40.2 ± 1.5 (%) DUSA  199.4 ± 10.4 N/A N/A  183.2 ± 13.6

With 0.15% Magnesium Stearate and 20 μg Glycopyrrolate Gelatin t = 0HPMC Gelatin Gelatin Pre-Con Gelatin DD 18.1 ± 0.4 18.2 ± 0.3 17.3 ± 0.518.2 ± 0.3 17.0 ± 1.2 FPD (μg) 10.1 ± 0.3  9.6 ± 0.2  8.8 ± 0.3  8.1 ±0.2  8.5 ± 0.4 FPF (%) 50.3 ± 1.3 47.8 ± 1.0 43.9 ± 1.5 40.5 ± 0.9 42.3± 1.9 DUSA N/A 16.5 ± 0.6 16.2 ± 0.9 N/A 16.8 ± 0.7 HPMC Gelatin GelatinGelatin Gelatin 30/65 25/60 30/65 30/65 30/60 t = 1 DD 17.6 ± 0.2 18.3 ±0.8 17.6 ± 0.1 15.2 ± 0.1 16.9 ± 0.5 FPD (μg)  9.4 ± 0.2  8.6 ± 0.5  7.7± 0.1  6.5 ± 0.2  7.1 ± 0.3 FPF (%) 46.8 ± 1.0 42.9 ± 2.5 38.7 ± 0.532.3 ± 0.9 35.5 ± 1.4 DUSA N/A 17.4 ± 1.4 16.8 ± 0.7 N/A 16.5 ± 1.4 t =3 30/65 DD 17.2 ± 0.2 17.8 ± 1.8 18.3 ± 0.1 16.2 ± 0.4 16.4 ± 0.4 FPD(μg)  9.1 ± 0.1  7.9 ± 0.3  7.5 ± 0.1  6.1 ± 0.2  5.8 ± 0.1 FPF (%) 45.8± 0.3 39.6 ± 1.3 37.3 ± 0.7 30.7 ± 0.8 28.8 ± 0.5 DUSA N/A 16.0 ± 0.716.7 N/A 15.7 ± 0.6

In each case using HPMC capsules, the FPF started at a higher levelrelative to the equivalent powders in gelatin capsules and remained high(at least 44%) over the 3 month period. In each case using gelatincapsules, the FPF started at the slightly lower level than had been seenwith HPMC capsules, but also in several instances dropped significantlyover the 3 month period to 30% or below.

This study supports the benefit of using a low moisture capsule inresolving the problem presented by micronised glycopyrrolate as outlinedabove.

This study also supports our belief that the basic aerosolisationprocess is more efficient with HPMC capsules compared to gelatincapsules. We believe this is due to the improved piercing of holesformed in the HPMC capsules.

EXAMPLE 6

As an alternative device, a prototype system termed the GyroHaler (asbriefly described above) was used. This device protects the formulationfrom moisture by containing the powder within pre-metered foil blisterstrips. Consequently, no moisture source is available to the powderproviding integrity of the seals is maintained.

In this study, blends containing 250 μg in 15 mg or 20 μg in 25 mgglycopyrrolate were made using the following method. This blendcomprised approximately 90% of Pharmatose 150 large carrier lactose,between approximately 9 and 10% Sorbolac 400, 0.15% magnesium stearateand the mictonised glycopyrronium bromide. The powders were blended in ahigh shear mixer, in one step.

The powder was metered into each foil blister which was subsequentlysealed with a foil lid. The device was actuated by allowing a piercinghead to pierce the blister lid. The powders were then drawn through themouthpiece and into a multi stage liquid impinger, at 60 l/min, usingthe method defined in the European Pharmacopoeia 2002. In each case, thefine particle fractions were between 45 and 50%. The fine particlefraction was defined here as the mass fraction smaller than 5 μmrelative to the delivered dose in each case.

EXAMPLE 7

The effect of conditioning on micronised glycopyrrolate wasinvestigated. An initial batch of glycopyrrolate ‘A’ was micronised at9.8 bar with feed rate of 0.2 kg/hour. This material was thenconditioned on a tray at 25° C./60% RH, with or withoutagitation/turning. Each of these powders was sized by Sympatec. Thepowders were then formulated using the method outlined in Example 4, as20 μg dose in 25 mg powder with 0.15% magnesium stearate and loaded intogelatin capsules. The fine particle fraction was assessed by firing thecapsules from a Miat MonoHaler device into a multi stage liquidimpinger, using the method defined in the European Pharmacopoeia 4^(th)Edition 2002. The fine particle fraction was defined here as the massfraction smaller than 5 μm relative to the nominal dose.

A second batch of glycopyrrolate ‘B’ was micronised at 9.8 bar with feedrate of 0.3 kg/hour. This powder was sized by Sympatec. The powder wasthen formulated using the method outlined in Example 4, as 20 μg dose in25 mg powder with 0.15% magnesium stearate and loaded into gelatincapsules. The fine particle fraction was assessed by firing the capsulesfrom a Miat MonoHaler device into a multi stage liquid impinger, usingthe method defined in the European Pharmacopoeia 4^(th) Edition 2002.The fine particle fraction was defined here as the mass fraction smallerthan 5 μm relative to the nominal dose.

A third batch of glycopyrtolate ‘C’ was micronised at 9.8 bar with feedrate of 0.4 kg/hour. This material was then conditioned on a tray at 25°C./60% RH, with or without agitation/turning. Each of these powders wassized by Sympatec. The powders were then formulated using the methodoutlined in Example 4, as 20 μg dose in 25 mg powder with 0.15%magnesium stearate and loaded into gelatin capsules. The fine particlefraction was assessed by firing the capsules from a Miat MonoHalerdevice into a multi stage liquid impinger, using the method defined inthe European Pharmacopoeia 4^(th) Edition 2002. The fine particlefraction was defined here as the mass fraction smaller than 5 μmrelative to the nominal dose.

A fourth batch of glycopyrrolate ‘D’ was micronised at 8.8 bar with feedrate of 0.4 kg/hour. This powder was sized by Sympatec. The powder wasthen formulated using the method outlined in Example 4, as 20 μg dose in25 mg powder with 0.15% magnesium stearate and loaded into gelatincapsules. The fine particle fraction was assessed by firing the capsulesfrom a Miat MonoHaler device into a multi stage liquid impinger, usingthe method defined in the European Pharmacopoeia 4^(th) Edition 2002.The fine particle fraction was defined here as the mass fraction smallerthan 5 μm relative to the nominal dose.

A fifth batch of glycopyrrolate ‘E’ was micronised at 7.8 bar with feedrate of 0.4 kg/hour. This material was then conditioned on a tray at 25°C./60% RH, with or without agitation/turning. Each of these powders wassized by Sympatec. The powders were then formulated using the methodoutlined in Example 4, as 20 μg dose in 25 mg powder with 0.15%magnesium stearate and loaded into gelatin capsules. The fine particlefraction was assessed by firing the capsules from a Miat MonoHalerdevice into a multi stage liquid impinger, using the method defined inthe European Pharmacopoeia 4^(th) Edition 2002. The fine particlefraction was defined here as the mass fraction smaller than 5 μmrelative to the nominal dose.

The results from each of the tests on batches A to E are sumnmarisedbelow. Batches A1, C1 and E1 were not conditioned. Batches A2, C2 and E2were conditioned at 25° C./60% RH and batches A3, C3 and E3 wereconditioned at 25° C./60% RH with turning. Feed T = 0 T = 2 wks rate D₅₀% MMAD MMAD GP (bar) (kg/h) D₉₀ μm μm D₁₀ μm FPD (μm) % FPD (μm) A1 9.80.2 3.68 1.95 0.81 34.7 2.8 30.5 3.2 A2 10.02 3.89 1.22 ND ND ND ND A39.78 4.03 1.24 34.5 2.8 31.5 3.1 B 9.8 0.3 4.25 2.14 0.85 ND ND ND ND C19.8 0.4 4.83 2.41 0.95 39.9 3.9 35.5 4.0 C2 7.84 3.76 1.24 39.2 3.3 34.03.6 C3 8.23 3.97 1.24 39.9 3.2 37.9 3.4 D 8.8 0.4 4.86 2.44 0.98 37.93.2 31.9 3.6 E1 7.8 0.4 4.88 2.47 1.01 39.9 3.3 33.3 3.4 E2 7.08 3.611.28 ND ND ND ND E3 7.85 3.79 1.23 38.7 3.2 32.7 3.7Mictonisation Trial Results

The Malvern particle size data show that particle size can be influencedby powder feed rate. The relationship between feed rate and particlesize obtained is probably non-linear. So, depending on how close theoperation is to the most sensitive conditions, an effect may or may notbe seen. Here an effect is seen. Similarly, an effect would be expectedwith milling pressure, but in contrast this data suggest between 8 and10 bar it appears to be above the pressure-sensitive conditions, solittle change in d50 is seen at constant feed rate.

In each case, the Malvern d50s grow significantly on exposure tomoisture, doubling diameter which probably represents formation of hardagglomerates of ˜8 primary particle equivalents. This is consistent withformation of solid bridges, as is anticipated from the amorphous tocrystalline transition. However, it is interesting to note that theMMADs produced from dispersion testing the formulations do not mirrorsuch growth when comparing the formulations.

It is suggested that the Malvern disperser has not been strong enough todestroy these solid bridges down to primary particles. However, themilling action occurring when these drug materials were blended in thehigh shear mixer with large lactose particles contained in thePharmatose 150M can be quite substantial (i.e. larger than approximately50 μm), and may well be sufficient to return the drug agglomerates toits primary size, at least transiently.

EXAMPLE 8

Mechanofused Glycopyrrolate with Magnesium Stearate

Blend 1: Micronised Glycopytrolate Bromide+5% Magnesium Stearate

A further study was conducted to look at the mechanofusion of the drugwith a force control agent. The force control agent used was magnesiumstearate. The blends were prepared by using the Hosokawa AMS-MINI system(Hosokawa Micron Ltd), blending 95% micronised glycopyrtolate bromidewith 5% magnesium stearate for 60 minutes at approximately 4000 rpm.

This powder was kept stored in a sealed bottle for approximately 4years. In order to determine the performance of this material after thistime, blends were produced and a selected formulation tested for aerosolperformance.

As the name suggests, mechanofusion is term referring to a dry coatingprocess designed to mechanically fuse a guest material onto a hostmaterial. The process was conducted here in order to achieve a drugpowder which was less susceptible to formation of solid bridges andrelated instability such as via re-crystallisation over time.

For mechanofusion the guest material is generally smaller and/or softerthan the host. The equipment used for mechanofusion are distinct fromalternative mixing and milling techniques in having a particularinteraction between one or more inner elements and a vessel wall, andare based on providing energy by a controlled and substantialcompressive force. Suitable equipment for mechanofusion includes theMechanoFusion range of systems made by Hosokawa, the Cyclomix range ofsystems made by Hosokawa, the Nobilta systems made by Hosokawa, theHybridiser made by Nara, and all related such systems. Mills such asball mills may also be used for this purpose, as can pin mills, discmills, mortar mills and other such mills. Jet mills may also be used.

In one embodiment, the powder is compressed between the fixed clearanceof the drum wall and one or more inner elements with high relative speedbetween drum and element. The inner wall and the curved element togetherform a gap or nip in which the particles are pressed together. As aresult, the particles experience very high shear forces and very strongcompressive stresses as they are trapped between the inner drum wall andthe inner element. The particles are pressed against each other withenough energy to locally heat and soften, break, distort, flatten andwrap the additive particles around the core particle to form a coating.The energy is generally sufficient to break up agglomerates and somedegree of size reduction of both components may occur.

An especially desirable aspect of the described processes is that theadditive material becomes deformed in the milling and may be smearedover or fused to the surfaces of the active particles.

For the purposes of this method, all forms of co-milling areencompassed, including methods similar or related to those methodsdescribed above. For example, methods similar to MechanoFusion areencompassed, such as those utilizing very high speed rotors (i.e. 1000to 50000 rpm) with elements sweeping the internal surfaces of thevessels with small gaps between wall and element (i.e. 0.1 mm to 20 mm).

Blend 2: Mechanofused Fine Lactose+1% Magnesium Stearate

Batches were prepared by combining 198 g Sorbolac 400 (Meggle) lactosewith 2 g magnesium stearate. The Cyclomix (Hosokawa Micron Ltd, set witha 1 mm gap) was set running at 200 rpm. Half the lactose was addedfollowed by the magnesium stearate and the remaining lactose. The speedwas slowly increased to run at 2000 rpm for 10 minutes.

Blend 3: Mechanofused Large Carrier Lactose+0.12% Magnesium Stearate

Batches were prepared by combining 199.76 g Respitose SV003 (DMV)lactose plus 0.24 g magnesium stearate. The Cyclonix (Hosokawa MicronLtd, set with a 1 mm gap) was set running at 200 rpm. Half the lactosewas added followed by the magnesium stearate and the remaining lactose.The speed was slowly increased to run at 2000 rpm for 10 minutes.

A combination of Blends 1, 2 and 3 comprising treated drug, fine andcoarse carrier lactose was prepared as follows: 90% Blend 3+9.5% Blend2+0.5% Blend 1. The powders were layered in a glass vessel. The vesselwas sealed and the powders blended in a Turbula tumbling blender at 37rpm for 10 minutes.

10 capsules were filled with 25 mg±5 mg of this powder in order totarget a dose of approximately 120 μg of glycopyrrolate. All 10 capsuleswere then were fired from a MonoHaler (Miat) at 70 l/min into a TSI.Stages 1 and 2 were analysed by UV spectroscopy at 220 nm. An averagefine particle fraction of 40% was calculated for this blend, where thefraction was calculated as that less than 5 μm.

This demonstrated that the drug powder has exhibited excellent stabilityover 4 year's storage, and was able to produce a good fine particlecloud on aerosolisation from an inhaler.

Conditioning of Micronised Drug Particles

The above example illustrates how micronised drug particles may beconditioned, in order to reduce the surface non-crystalline materialpresent. The conditioning involves exposing the glycopyrrolate to humidconditions of 30-100 RH, preferably 40-95 RH, 45-95 RH or 50-90 RH. Theglycopyrrolate powder is preferably placed on a tray for this step andthe powder is preferably agitated or turned to ensure that all of theparticles are equally exposed to the humid atmosphere. The turning oragitating also helps to avoid or reduce agglomeration of the particlesduring the conditioning process. The conditioning preferably takes placeover a period of at least about 10 minutes, at least about 20 minutes,at least about 30 minutes, at least about 40 minutes, at least about 50minutes, at least about 1 hour, at least about 2, 3, 4, 5, 6, 8, 10, 12,14, 18, 24, 36 or 48 hours.

Conditioning may also be achieved in a variety of alternative ways. Somefurther general approaches are outlined below.

Particles extracted from the dynamic micronisation process are collectedand may be transported to a suitable vessel for conditioning at acontrolled humidity. In such a system, preferably the particles are allexposed to the humidity for sufficient time for the water absorption andfor the re-crystallisation process to occur. Preferably all the powderremains in the vessel from start to finish of this process.

If the micronisation process itself were conducted using gas at elevatedhumidity, this exposure would be less easy to control. While powdercould be conditioned in the collection system, powder added at the endof the process would have less time to condition than powder added atthe start.

The Relative Humidity may be in the range 30 to 100%, more preferably 40to 950%, more preferably 45 to 95% and most preferably 50 to 90%. Thetemperature may be varied, and preferably be in the range 5° C. to 90°C., more preferably 10° C. to 50° C.

The vessel may be for example a tray, or a bag. It should allow suitableexposure of the powder surface to the moisture applied from theatmosphere. The powder may be agitated or not agitated. If the powder isplaced on a tray, it is preferably spread evenly in a relatively thinlayer over the tray.

As an alternative, the micronised powder may be transferred to a systemwhich creates a fluidised bed of the mictonised powder. Such systems areknown in the art. The micronised powder is difficult to fluidise alone,and consequently fluidisation media are advantageously added, such asmetal, plastic, glass or ceramic beads, typically with diameters in therange 100 μm to 5 mm.

A fluidised bed aerosol technique for this purpose could be one asdescribed by Morton et al (J. Aerosol Science, Vol. 26, No. 3, p 353 andreferences therein).

1: A dry powder formulation comprising glycopyrrolate, wherein theformulation is stable over a period of at least 1 year under normalconditions. 2: A dry powder formulation as claimed in claim 1, whereinthe formulation is stable over a period of at least 2 years. 3: A drypowder formulation as claimed in claim 1, wherein the formulation isstable over a period of at least 3 years. 4: A dry powder formulation asclaimed in claim 1, wherein instability of the formulation is indicatedby the formation of hard agglomerates. 5: A dry powder formulation asclaimed in claim 1, wherein stability of the formulation is indicated byconsistent good fine particle fraction or fine particle dose values. 6:A dry powder formulation as claimed in claim 5, wherein the fineparticle fraction of the powder is consistently at least about 30%. 7: Adry powder formulation as claimed in claim 6, wherein the fine particlefraction of the powder is consistently at least about 40%. 8: A drypowder formulation as claimed in claim 1, wherein stability of theformulation is achieved by preventing or reducing the uptake of moistureby the formulation. 9: A dry powder formulation as claimed in claim 1,wherein the glycopyrrolate is micronised. 10: A dry powder formulationas claimed in claim 9, wherein the glycopyrrolate is conditioned duringor following micronisation to reduce the tendency of the formulation toabsorb moisture. 11: A dry powder formulation as claimed in claim 10,wherein the conditioning involves controlled exposure of theglycopyrrolate to moisture. 12: A dry powder formulation as claimed inclaim 10, wherein the conditioning involves disruption of any solidbridges formed during or following micronisation. 13: A dry powderformulation as claimed in claim 1, wherein the formulation furthercomprises a force control agent which is capable of reducing cohesionbetween the fine particles in the formulation. 14: A dry powderformulation as claimed in claim 13, wherein the force control agent alsoacts as a surfactant. 15: A dry powder formulation as claimed in claim13, wherein the force control agent prevents the ingress of moistureinto the formulation.
 16. (canceled) 17: A dry powder formulation asclaimed in claim 1, wherein the formulation is stored in packaging madefrom a material which has a moisture content of less than 10%. 18: A drypowder formulation as claimed in claim 17, wherein the packagingmaterial has a moisture content of less than 5%. 19: A dry powderformulation as claimed in claim 17, wherein the packaging material has amoisture content of less than 3%. 20: A dry powder formulation asclaimed in claim 17, wherein the packaging is an HPMC capsule. 21: A drypowder formulation as claimed in claim 1, wherein the formulation isstored in packaging which is capable of preventing the ingress ofmoisture form external sources. 22: A dry powder formulation as claimedin claim 21, wherein the packaging is a foil sealed blister. 23: A drypowder formulation as claimed in claim 17, wherein the packaging isitself protected from the ingress of moisture from external sources. 24:A dry powder inhaler device comprising a dry powder formulation asclaimed in claim
 1. 25: A method of preparing a dry powder formulationas claimed in claim 1, wherein the glycopyrrolate is micronised and themicronisation process is performed under conditions which reduce theformation of amorphous material and/or wherein the glycopyrrolate isconditioned to reduce the amorphous material content. 27: A method asclaimed in claim 26, wherein the conditioning involves controlledexposure of the glycopyrrolate to moisture. 28: A method as claimed inclaim 26, wherein the conditioning involves disruption of any solidbridges formed during or immediately following micronisation. 29: Amethod as claimed in claim 25, wherein a force control agent which iscapable of reducing cohesion between the fine particles in theformulation is added to the glycopyrrolate.
 30. A dry powder formulationas claimed in claim 13, wherein the force control agent is magnesiumstearate, one or more amino acids or their derivatives, lecithin orphospholipids 31: A dry powder formulation as claimed in claim 30,wherein the amino acid is leucine, lysine, arginine, histidine orcysteine, or derivatives thereof.